Cholinergic transmission in the striatal complex is critical for the modulation of the activity of local microcircuits and dopamine release. Release of acetylcholine has been considered to originate exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre ϩ transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.

Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

This paper describes experimental techniques with head-fixed, operantly conditioned rodents that allow the control of stimulus presentation and tracking of motor output at hitherto unprecedented levels of spatio-temporal precision. Experimental procedures for the surgery and behavioral training are presented. We place particular emphasis on potential pitfalls using these procedures in order to assist investigators who intend to engage in this type of experiment. We argue that head-fixed rodent models, by allowing the combination of methodologies from molecular manipulations, intracellular electrophysiology, and imaging to behavioral measurements, will be instrumental in combining insights into the functional neuronal organization at different levels of observation. Provided viable behavioral methods are implemented, model systems based on rodents will be complementary to current primate models—the latter providing highest comparability with the human brain, while the former offer hugely advanced methodologies on the lower levels of organization, for example, genetic alterations, intracellular electrophysiology, and imaging.

The nucleus accumbens (NAc) plays a role in conditioned place preference (CPP). The authors tested the hypothesis that inhibition of mitogen-activated protein kinases (MAPKs) would inhibit NAc-amphetamine-produced CPP. Results confirmed that NAc amphetamine increased levels of the MAPK extracellular signal-regulated kinase (ERK). In CPP studies, NAc injections (0.5 microl per side) of the ERK inhibitor PD98059 (1.0-2.5 microg) or the p38 kinase inhibitor SB203580 (15-500 ng) dose dependently impaired CPP. The c-Jun-N-terminal kinase (JNK) inhibitor SP600125 (1.0-2.5 microg) failed to block the CPP effect. The drugs did not block amphetamine-induced motor activity. Results suggest that ERK and p38, but not JNK, MAPKs may be necessary for the establishment of NAc amphetamine-produced CPP and may also mediate other forms of reward-related learning dependent on NAc.

Understanding the neural code underlying perception requires the mapping of physical stimulus parameters to both psychophysical decisions and neuronal responses. Here, we employed a novel psychophysical task in head-fixed rats to measure discriminability of vibrotactile whisker deflections. Rats could discriminate 90 Hz from 60 Hz pulsatile stimuli if stimulus intensity covaried with frequency. To pin down the physical parameters used by the rats to discriminate these vibrations, we manipulated stimulus amplitude to arrive at pairs of nondiscriminable stimuli. We found that vibrations matched in intensity (measured as mean absolute velocity), but differing in frequency, were no longer discriminable. Recordings of trigeminal ganglion neurons revealed that the distribution of neurometric sensitivities based on spike counts, but not interspike intervals, matched the rats' inability to discriminate intensity-matched stimuli. In conclusion, we suggest that stimulus mean absolute velocity, encoded in primary afferent spike counts, plays a prominent role for whisker-mediated perception.

Acetylcholine in the striatal complex plays an important role in normal behavior and is affected in a number of neurological disorders. Although early studies suggested that acetylcholine in the striatum (STR) is derived almost exclusively from cholinergic interneurons (CIN), recent axonal mapping studies using conditional anterograde tracing have revealed the existence of a prominent direct cholinergic pathway from the pedunculopontine and laterodorsal tegmental nuclei to the dorsal striatum and nucleus accumbens. The identification of the importance of this pathway is essential for creating a complete model of cholinergic modulation in the striatum, and it opens the question as to whether other populations of cholinergic neurons may also contribute to such modulation. Here, using novel viral tracing technologies based on phenotype-specific fluorescent reporter expression in combination with retrograde tracing, we aimed to define other sources of cholinergic innervation of the striatum. Systematic mapping of the projections of all cholinergic structures in the brain (Ch1 to Ch8) by means of conditional tracing of cholinergic axons, revealed that the only extrinsic source of cholinergic innervation arises in the brainstem pedunculopontine and laterodorsal tegmental nuclei. Our results thus place the pedunculopontine and laterodorsal nuclei in a key and exclusive position to provide extrinsic cholinergic modulation of the activity of the striatal systems.

Reward-related incentive learning involves the acquisition by neutral stimuli of an enhanced ability to elicit approach and other responses. Previous studies have shown that both dopamine (DA) and glutamate (Glu) play critical roles in this type of learning. Signaling molecules are intracellular messengers that participate in the influence of transmitter-receptor events on intracellular function including transcription in the nucleus. In recent years studies have begun to implicate signaling molecules in incentive learning. Thus, inhibition of cyclic adenosine monophosphate-dependent protein kinase (PKA) in the nucleus accumbens (NAc), that is activated by DA acting at D1-like receptors, blocks the acquisition of conditioned approach responses, lever pressing for food, conditioned place preference (CPP) based on NAc injections of amphetamine or cocaine, and conditioned activity based on NAc injections of amphetamine. Similar effects have been observed with PKA inhibition in the basolateral amygdala or medial prefrontal cortex. If animals were trained prior to testing with PKA inhibitors in NAc, no effect was seen suggesting that PKA is more important for acquisition than expression of incentive learning. Inhibition of calcium-dependent protein kinase or mitogen-activated protein kinases in NAc similarly has been shown to block the acquisition of incentive learning. Results support a model of DA-Glu synaptic interactions that form the basis of incentive learning.

The action-based model of dissonance and recent advances in neuroscience suggest that commitment to action should cause greater relative left frontal cortical activity. An induced compliance experiment was conducted in which electroencephalographic activity was recorded following commitment to action, operationalized with a perceived choice manipulation. Perceived high as compared to low choice to engage in the counterattitudinal action caused attitudes to be more consistent with the action. Also, high choice caused greater relative left frontal cortical activity than low choice. Copyright # 2006 John Wiley & Sons, Ltd.The original theory of dissonance (Festinger, 1957) posited that inconsistency among important elements of knowledge (cognitions) creates dissonance, an unpleasant emotional-motivational state. This state was presumed to cause organisms to do cognitive work in an attempt to reduce the dissonance. The original theory used the same word, 'dissonance,' to describe both the discrepancy between cognitions and the emotive state provoked by this discrepancy. To improve clarity about the processes, we use the terms 'dissonance' or 'dissonance arousal' to describe the emotive state and the term 'cognitive discrepancy' to describe the inconsistency between cognitions. When dissonance is evoked, and organisms reduce it by changing their 'cognitive world' (i.e., attitudes, beliefs, or behaviors), we refer to the process as 'discrepancy reduction.' When the negative emotionalmotivational state is successfully eliminated or reduced, we call this 'dissonance reduction. ' Several revisions have been proposed to explain the data generated by dissonance theory. Some revisions focused on the role of the self-concept or self-esteem as being important in dissonance